1-oxo and 1,1-dioxo-3-isothiazolones

ABSTRACT

NOVEL COMPOUNDS OF THE 1-OXO- AND 1,1-DIOXO-3-ISOTHIAZOLONE CLASS OF COMPOUNDS WHICH INCLUDE 2-ALKYL, 2ARYL, 2-CARBAMOYL AND 4- AND 5-ALKYL AND HALO DERIVATIVES. THESE COMPOUNDS ARE USEFUL AS PESTICIDES.

3,562,283 l-OXO AND 1,1-DIOX-3-ISOTHIAZOLONES Sheldon N. Lewis, Willow Grove, and George A. Miller, Glenside, Pa., assignors to Rohm and Haas Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Filed July 1, 1968, Ser. No. 741,257 Int. Cl. C07d 91/10 US. Cl. 260-301 Claims ABSTRACT OF THE DISCLOSURE Novel compounds of the l-oxoand 1,1-dioxo-3-isothiazolone class of compounds which include 2-alkyl, 2- aryl, Z-carbamoyl and 4- and S-alkyl and halo derivatives. These compounds are useful as pesticides.

This invention is concerned with l-0X0-3-is0thiaz0lone, 1,l-dioxo-3-isothiazolone and nuclear substituted derivatives thereof as new compounds and with their method of preparation.

These novel 3-isothiazolones may be represented by the formula NY l S/ wherein Y is hydrogen, alkyl of 1 to 18 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; aralkyl of up to 10 carbon atoms; halogen, lower alkyl or lower alkoxy substituted aralkyl of up to 10 carbon atoms; aryl, halogen, methyl or nitro substituted aryl; lower hydroxyalkyl, lower haloalkyl, lower carbalkoxyalkyl; lower cyanoalkyl; lower carboxyalkyl; or a carbamoyl group of the structure wherein R is an alkyl group of 1 to 18 carbon atoms, the group CH COOR wherein R is alkyl of 1 to 18 carbon atoms, aryl or halo-substituted aryl; R and R are individually selected from the group consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms, halogen atoms and phenyl; and metallic, amine and quaternary ammonium salts of those compounds when Y is hydrogen or lower carboxyalkyl; and n is the integer l or 2.

Where the expression lower is employed in conjunction with terms such as alkyl, alkoxy, and various substituted alkyls, it is intended to indicate that the alkyl or alkyl portion thereof has a carbon content of 1 to 4 carbon atoms. Typically, the alkyl or alkyl portion may be methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.

The preferred structures corresponding to Formula I are those in Whcih Y is hydrogen, alkyl of 1 to 18 carbon atoms, aryl, halosubstituted aryl or the carbamoyl group C(O)NHR as defined above.

When Y is hydrogen the compounds may exist in their isomeric form as the 3-hydroxyisothiazoles of the general structure (0)n (II) For the purpose of this invention the compounds shall be referred to as derivatives of 3-isothiazolone.

Typical compounds within the scope of Formula I include the following:

1-oxo-3 -isothiazolone 1-oxo-2-methy1-3-isothiazolone United States Patent Office 3,562,283 Patented Feb. 9, 1971 1-oxo-2-isopropyl-3-isothiazolone 1-oxo-2-sec-butyl-3 -isothiazolone 1-oxo-2-t-butyl-B-isothiazolone 1-oxo-2-pentyl-3-isothiazolone 1-0xo-2-hexyl-3-isothiazolone 1-oxo-2-heptyl-3-isothiazolone 1-oxo-2-octyl-3-isothiazolone 1-oxo-2-dodecyl-3 -isothiazolone 1-oxo-2-octadecyl-3-isothiazolone l-oxo-4-methyl-3 -isothiazolone 1-oxo-4ethyl-3 -isothiazolone 1-oxo-4-butyl-3-isothiazolone 1-oxo-4-fluoro-3-isothiazolone 1-oxo-4-chloro-3-isothiazolone 1-oxo-4-bromo-3-isothiazolone 1-oxo-5-propyl-3 -isothiazolone 1-oxo-4-sec-butyl-3-isothiazolone 1-oxo-4,5-dimethyl-3-isothiazolone 1-oxo-4-methyl-5 -ethyl-3-isothiazolone 1-oxo-4-isopropyl-5-chloro-3-isothiazolone l-oxo-4-chloro-5-ethyl-3-isothiazolone 1-oxo-4-bromo-5-isopropyl-3 -isothiazolone 1-0xo-2-t-octyl-4-chloro-5-methyl-3 -isothiazo1one 1-oxo-2-phenyl-3-isothiazolone l-oxo-Z- (3 ,4-dichlorophenyl -4-ethy1-3-is0thiaz0lone 1-oxo-2- 4-chlorophenyl -4,5-dichloro-3-isothiazolone 1-oxo-2- (propylcarbamoyl) -3-isothiazolone 1-oXo-2- (methylcarbamoy1) -4-chloro-3 -isothiazolone 1-oXo-2- (ethylcarbamoyl -4-chloro-5-methyl-3- isothiazolone 1-oXo-2- (phenylcarbarnoyl) -3-isothiazolone l-oxo-Z- 3 ,4-dichlorophenyl) -5-methyl-3 -isothiazolone 1-oxo-2- N-carb omethoxymethylcarb amoyl) -3 isothiazolone l-oxo-Z- (N-carbethoxymethylcarbamoyl) -4-chloro-3- isothiazolone 1-oXo-2- (N-carbobutoxymethylcarbamoyl -4-methy1- 5-chloro-3 -isothiazolone 1-oXo-2-cyclohexyl-3-isothiazolone 1-oXo-2-benzyl-3-isothiazolone l-oxo-2- 2-hydroxyethyl) -3-isothiazolone l-oxo-2- 2-chloroethyl) 3-isothiazolone 1-oXo-2-cyanomethyl-3 -isothiazolone l-oXo-2-carboxymethyl-3-isothiazolone l-oXo-2- (2-carbomethoxyethyl) -3 -isothiazolone 1,1-dioXo-3 -isothiazolone 1,1-dioxo-2-methyl-3isothiazolone -dioxo-2-propyl-3-isothiazolone dioxo-2-decyl-3-isothiazolone ioxo-2-octadecyl-3-isothiazolone 1oxo-4-methyl-3-isothiazolone 1oxo-4-propyl-3-isothiazolone 1oxo-4-t-butyl-3-isothiazolone ioxo-4-chloro-3-isothiaz0lone ioxo-4-bromo-3-isothiazolone oxidized to the 1,1-dioxo derivative. The following equation depicts these reactions.

Oxidation of the sulfur atom in a 3-isothiazolone ring was not known in the literature prior to this invention.

Oxidations of isothiazole ring structures have been reported by N. R. Hatchard Journal Organic Chemistry 29, 667 (1964) and in C. A. 67, 90715 citing A. Bruno et a1. Gazz. chim ital. 96, 1009-19 (1966).

Various types of oxidizing agents may be employed, e.g. peracids such as hydrogen peroxide, performic acid, peracetic acid, perphthalic acid, perbenzoic acid and mchloroperbenzoic acid; oxides of nitrogen such as dinitrogen tetroxide; nitric acid; and chromic compounds such as chromium trioxide and chromic acid-sulfuric acid (Jones reagent).

When peracids (RCO H) are employed for the oxidation and the l-oxo derivative is desired, it is preferred to use no more than one equivalent of the peracid. To prepare the 1,1-dioxo derivative at least two equivalents are theoretically required, but three or more equivalents may be used. Although the oxidations may be run in the absence of a solvent, the use of a solvent is preferred. Any solvent which is not itself oxidized may be used and solvents in the ester, ketone, aliphatic and aromatic hydrocarbon and chlorinated hydrocarbon classes are commonly employed. The chlorinated aliphatic hydrocarbons are preferred. Temperaturewise the reactions may be run in the range of --5 to 60 C. with lower temperatures, e.g. to 15 C., being preferred for the l-oxo derivatives and higher temperatures, e.g. -25 C., being preferred for the 1,1-dioxo derivatives.

When an oxide of nitrogen such as N 0,, is employed at least one equivalent is theoretically required for conversion to the l-oxo derivative. With this type of oxidizing agent, oxidation to the 1,1-dioxo stage is more difiicult and even with excesses of the dinitrogen tetroxide the major product is the l-oxo derivative. An inert solvent, for example from the ether and chlorinated classes of solvents, is commonly employed although the reaction will proceed in the absence of a solvent. The reaction is usually run in the temperature range of 5 to 35 C. with 0 to C. being preferred. In some instances the nitric acid salt of the 3-isothiazolone forms and this upon mild heating is converted to the l-oxo derivative.

When nitric acid is used as the oxidizing agent, the acid may have a concentration in the range of to 70% with 65 to 70% being preferred. The reaction temperature may be in the range of 5 to 35 C. with 0 to 15 C. being preferred. The usual product is the l-oxo derivative, which may be formed from the nitrate salt by mild heating, e.g. in benzene, which is illustrated for 3-isothiazo1one as follows:

When chromic acid is used as the oxidizing agent it may be employed in from 0.5 to 2 or more equivalents. The l-oxo derivative is readily formed. The 1,1-dioxo derivative is more difficult to prepare and isolate. An inert solvent, such as a ketonic solvent, is commonly employed although the oxidation will proceed in the absence of a solvent. The reaction is usually run at about room temperature, but will proceed at 0 to 60 C. with 15 to 35 C. being preferred.

Since the possibility existed that oxidation could occur on the N atom of the isothiazolone nucleus, the compounds were examined by spectral and other physical means to distinquish between -NO and -S0 or SO oxidized ring structures. For example structures such as and could have been formed. Infrared absorption data showed a strong sulfoxide absorption in the 9.0-9.4,u range for the mono-oxidized products and a strong sulfonyl absorption at 7.55 and 8.4-8.7 for the dioxidized materials. These data are consistent for the literature values for characteristic sulfoxide and sulfonyl absorptions and not in conformance with N-oxide absorption of related structures. Ultraviolet absorption data, nuclear magnetic resonance data and mass spectra lead to the same conclusion that the products are l-oxo and 1,1-dioxo-3- isothiazolones.

Alternate methods of preparation by which the compounds of this invention may be made include (a) reaction of R l l o -L (0).. wherein R, R Y and n have the meanings given above, and (b) where Y is a C(O)NHR group by reaction of R l l with YNHz are available by methods described in Lewis and Miller patent application U.S. Ser. No. 621,770, filed Mar. 9, 1967 and Lewis, Miller and Law US. Ser. No. 672,437, filed Oct. 3, 1967 assigned to a common assignee and which are incorporated herein by reference.

By way of demonstration the following examples are offered to illustrate this invention and are not to be construed as limitations thereof. Table I lists Examples 1-14 of the l-oxo derivatives and Table II lists Examples 15-19 of the 1,1-dioxo derivatives. Table III lists the method of preparation, yields and melting points for these examples. Table IV gives analytical data for these examples-Specific illustrative preparations of Examples 1, 2 and 15 are set forth below.

EXAMPLE 1.P-REPARAT ION OF l-OXO- B-ISOTHIAZOLONE Method A.Oxidatin of a 3-isothiaz0lone with a peracid To a solution of 10.1 g. (0.1 mole) of 3-isothiazolone in 100 ml. of methylene chloride was added dropwise at 0-10 C. a solution of 21.3 g. (0.1 mole) of m-chloroperbenzoic acid (81% by iodide-thiosulfate titration) in 200 ml. of methylene chloride. The reaction mixture was stirred 0.5 hour and then evaporated to dryness. The residue, after trituration with ether, was 7.1 g. of solid which after recrystallization from benzene melted at 95 96 C. This is a 60% yield of 1-oxo-3-isothiazolone.

Method B.--Oxidation of a 3-isothiazolone with dinitrogen tetroxide To a solution of 20.2 g. (0.2 mole) of 3-isothiazolone in 150 ml. of ether at 010 C. was added a solution of 18.4 g. (0.2 mole) of N 0,, in 25 ml. of hexane over a period of 5 minutes. The reaction slurry was stirred minutes then filtered to give 21 g. of solid melting at 81 85 C., which is considered to be 3-hydroxyisothiazole nitrate salt. This salt when crystallized from hot benzene gave off brown fumes of an oxide of nitrogen. The benzene solution upon cooling yielded 14 g. of solid melting at 93-95 C. This is a 60% yield of 1-oxo-3-isothiazolone.

When the above reaction was carried out at 10-20 C. there was directly obtained a 70% yield of 1-oxo-3-isothiazolone without the intermediate isolation of 3-hydroxyisothiazole nitrate salt.

Method C.--Oxidation of 3-isothiazolone with nitric acid A solution of 5 g. (0.05 mole) of 3-isothiazolone in 30 m1. of water was added to 50 g. of concentrated (70%) nitric acid at 0 C. A solid formed and after stirring 15 minutes at 0 C. was filtered OE and dried to give 6.2 g. of a solid melting at 93 95 C. from ethanol. The solid was found by analysis to contain 21.92% C, 2.03% H, 16.18% N and 19.21% S; calculated for C H N O S is 22.1% C, 1.84% H, 17.1% N and 19.6% S. The solid is a 76% yield of 3-hydroxyisothiazole nitrate salt. Two grams of this salt when crystallized from hot benzene gave evolution of nitrogen dioxide and yielded 0.5 g., a 35% yield, of 1-oxo-3-isothiazolone, melting at 9294 C.

EXAMPLE 2.PR EPARATION OF l-OXO- 5-METHYL-3-ISOTHIAZOLONE Method D.-Oxidation of a 3-isothiazolone with chromic acid A solution of 11.5 g. (0.1 mole) of 5-methyl-3-isothiazolone in 750 ml. of acetone (purified by distillation from solid potassium permanganate) was treated dropwise at 25 C., under a continuous stream of nitrogen, with 50 ml. of Jones Reagent (0.2 mole of oxidant) made by dissolving 26.7 g. of chromium trioxide in 23 ml. of concentrated sulfuric acid and then diluting with water to 100 ml. over a period of 1.5 hour. After stirring at room temperature for 18 hours, the reaction was concentrated to 25 g. of green, liquid residue. The residue was diluted with 100 ml. of Water and continuously extracted 24 hours to give, after drying and evaporation of the ether, 9.5 g. of light yellow oil. This is a yield of l-oxo-S-methyl- 3-isothiazolone.

EXAMPLE 15.PREPARATION OF 1,1-DIOXO- S-ISOTHIAZOLONE Method E.-Oxidation of a 3-isothiazolone A solution of 10.1 g. (0.1 mole) of 3-isothiazolone in 200 ml. of methylene chloride was treated in portions with 47.3 g. (0.22 mole) of 81% pure m-chloroperbenzoic acid. A slurry resulted and was stirred at room temperature for 2 days. The residue was filtered off and extracted with hot chloroform to give 6.65 g. of insoluble solid melting at ll8120 C. This is a 49% yield of 1,1-dioxo-3- isothiazolone.

Method F.Oxidation of 1-oxo-3-isothiazolone A solution of 2.85 g. (0.024 mole) of 1-oxo-3-isothiazolone in ml. of methylene chloride was treated in portions at 25 C. with 5.17 g. (0.024 mole) of 81% pure m-chloroperbenzoic acid. The resulting slurry was stirred 2 days at room, temperature. The reaction mixture was evaporated to dryness and the residue triturated twice with benzene. There was obtained 1.7 g. of insoluble residue melting at 113-118 C. This is a 53% yield of 1,1-dioxo- 3-isothiazolone.

TABLE I.-1-OXO-3-ISOTHIAZOLONE EXAMPLES Name Example No.1

gmmmommmmm Name TABLE II.-1,1-DIOXO-3-ISOTHIAZOLONE EXAMPLES Example No.

fungi Aspergillus niger (A. niger), Rhizopus spp. (Rhiz.)

Thetaiglnovilr 1-g) o1 ar d 1,1-d1o (0-3-1sothiazo1on s of this and Rhodotorula spp. (Rhod.) and three algae Chlorella o d h e 10 8 3 actlve. Bepresentauve compyrenoidosa (Chlorella), Scenedesmus obliquus (Scene.) p un s ave effective control of vanous types of weeds, 75 and Phormidium spp. (Square D).

inven TABLE V.CONTROL OF MICROORGANISMS (RANK IN STREAK TEST) P. aeru- Square ginosa S. aureus E. coli A. niger Rhiz. Rhod. Chlorella Scene.

TABLE VI.SERIAL DILUTION TEST S. aureus Ecoli Exaiinple:

Representative compounds of this invention Were evaluated as fungicides in standard greenhouse tests. The compound of Example 3 when used to treat corn seed at a rate of 1 oz. per bushel gave good protection of the seed when planted in soil infested with Pythium sp. The compound of Example 6 gave good protection of rice by a foliar spray containing 1200 p.p.m. against Helminthosporium oryzae and of beans by a foliar spray containing 150 p.p.m. against Erysiphe polygoni. Tomato foliage was protected against the bacterial canker disease, Corynebacterium michiganense by an aqueous spray containing 1200 p.p.m. of the compound of Example 8. The compound of Example 13 as a spray containing 1200 p.p.m. protected tomato plants from late blight, Phytophthora infestants. The compound of Example 18 at 1200 p.p.m. gave excellent protection against Colynbacterium michiganense, Phytophthora infestants, the rice blast disease Piricularia oryzae and downy mildew of grapes Plasmopara viticola.

In standard greenhouse tests on the various stages of the two-spotted mite, Tetranychus urticae, using sprays containing 1% of the active ingredient the compound of Example 6 gave a 50% control of the mite eggs and 100% control of the adult mites, the compounds of Examples 8 and 9 gave 100% control as mite ovicides, and the compound of Example 13 gave 90% control of the mite larvae. As a 1% spray the compound of Example 2 gave a 60% control of the cabbage looper, Trichoplusia m, and the compound of Example 3 gave excellent control of the root knot nematode, Meloidogyne hapla.

Representative compounds of this invention were evaluated in a standard postemergence type herbicide test.

TABLE VII.HERBIOIDAL DATA Percent injury Monocots Dicots Example:

In general, loci subject to attack by microorganisms may be protected in accordance with this invention by incorporating into said loci one or more of the 'l-oxo and 1,l-dioxo-3-isothiazolones in an amount which is efiective to control said microorganisms. The exact amount of the 3-isothiazolone will, of course, vary with the medium being protected, the microorganisms being controlled, the particular compound or composition being employed and the like. Commonly this is the range of from 0.1 to 10,000 p.p.m.

For use as pesticides the compounds of this invention may be used as solutions in organic solvents or formulations. For example they may be formulated as wettable powders, emulsifiable concentrates, dusts, granular formulations or flowable emulsifiable concentrates. In such formulations the 1-oxo and l,1-dioxo-3-isothiazolones are extended with an agronomically acceptable liquid or solid carrier and, when desired, suitable surfactants are likewise incorporated. Surfactants commonly used in the art may be found in the John W. McCutcheon, Inc. publication Detergents and Emulsifiers 1967 Annual.

The isothiazoloes may be taken up on or mixed with a finely particled solid carrier, as for example, clays, in organic silicates, carbonates, and silicas. Organic carriers may also be employed. Dust concentrates are commonly made wherein isothiazolones are present in the range of 20 to 80%. For ultimate applications, these concentrates 11 are normally extended with additional solid from about 1 to 20%.

Wettable powder formulations are made by incorporating the compounds of this invention in an inert, finely divided solid carrier along with a surfactant which may be one or more emulsifying, wetting, dispersing or spread ing agents or blend of these. The isothiazolones are usually present in the range of 10 to 80% by weight and surfactants in from 0.5 to 10% by weight.

One convenient method for preparing a solid formulation is to impregnate the isothiazolone toxicant onto the solid carrier by means of a volatile solvent, such as acetone. In this manner, adjuvants, such as activators, adhesives, plant nutrients, synergists and various surfactants may also be incorporated.

Emulsifiable concentrate formulations may be prepared by dissolving the isothiazolones of this invention in an agronomically acceptable organic solvent and adding a solvent-soluble emulsifying agent. Suitable solvents are usually water-immiscible and may be found in the hydrocarbon, chlorinated hydrocarbon, ketone, ester, alcohol and amide classes of organic solvents. Mixtures of solvents are commonly employed. The surfactants useful as emulsifying agents may constitute about 0.5 to 10% by weight of the emulsifiable concentrate and may be anionic, cationic or non-ionic in character. The concentration of the active ingredients may vary from 10 to 80%, preferably in the range of 25 to 50% For use as phytopathogenic agents, these compounds should be applied in an effective amount sufficient to exert the desired biocidal activity by techniques well known in the art. Usually, this will involve the application of the isothiazolones to the loci to be protected in an effective amount when incorporated in an agronomically acceptable carrier. However, in certain situations it may be desirable and advantageous to apply the compounds directly onto the loci to be protected without the benefit of any substantial amount of carrier. This is a particularly effective method when the physical nature of the isothiazolones is such as to permit what is known as low-volume application, that is, when the compounds are in liquid form or substantially soluble in higher boiling solvents.

The application rate will, of course, vary depending upon the purpose for such application, the isothiazolones being utilized, the frequency of dissemination and the like.

For use as miticides, insecticides, agricultural bactericides and fungicides, dilute sprays may be applied at concentrations of 0.05 to 20 pounds of the active isothiazolone ingredient per 100 gallons of spray. They are usually applied at 0.1 to 10 pounds per 100 gallons and preferably at 0.125 to 5 pounds per 100 gallons. In more concentrated sprays, the active ingredient is increased by a factor of 2 to 12. With dilute sprays, applications are usually made to the plants until run-off is achieved, whereas with more concentrated or low-volume sprays the materials are applied as mists.

For use as herbicides the compounds may be applied at a rate of 0.25 to 50 pounds of the active ingredient per acre and preferably in the range of 1 to 15 pounds per acre.

The compounds of this invention may be utilized as the sole biocidal agents or the may be employed in conjunction with other bactericides, fungicides, herbicides, insecticides, miticides and comparable pesticides.

12 We claim: 1. A compound of the formula 1 N-Y R1 \S/ wherein Y is hydrogen, alkyl of 1 to 18 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; benzyl of up to 10 carbon atoms; halogen, lower alkyl or lower alkoxy substituted aralkyl of up to 10 carbon atoms; phenyl; halogen, methyl or nitro substituted phenyl; lower hydroxyalkyl, lower haloalkyl, lower carbalkoxyalkyl; lower cyanoalkyl; lower carboxyalkyl; or a carbamoyl group of the structure C(O)'NHR wherein R is an alkyl group of 1 to 18 carbon atoms, the group -CH COOR wherein R is alkyl of 1 to 18 carbon atoms, phenyl or halosubstituted phenyl; R and R are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, halogen atoms and phenyl; and n is the integer l or 2.

2. A compound of the formula R l-O .la-

wherein Y is hydrogen, alkyl of 1 to 18 carbon atoms, phenyl, halo-substituted phenyl or a carbamoyl group of the structure C(O)NHR wherein R is an alkyl group of 1 to 18 carbon atoms, the group CH COOR wherein R is alkyl of 1 to 18 carbon atoms, phenyl or halosubstituted phenyl; R and R are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and halogen atoms; and n is the integer 1 or 2.

3. The compounds of claim 1 wherein n of the formula is 1.

4. The compounds of claim 1 wherein n of the formula is 2.

5. The compound of claim 1 which is 1-ox0-3-isothiazolone.

6. The compound of claim 1 which is 1,1-dioxo-3-isothiazolone.

7. The compound of claim 1 which is 1-oxo-4-bromo- 5-methyl-3-isothiazolone.

8. The compound of claim 1 which is 1-oxo-2-(3,4- dichlorophenyl) -4-methyl-3-isothiazolone.

9. The compound of claim 1 which is 1-oxo-2-(N- e thylcarbamoyl) -3-isothiazolone.

10. The compound of claim 1 which is 1,1-dioxo-2- (3,4-dichlorophenyl)-4-methy1-3-isothiazolone.

References Cited UNITED STATES PATENTS 3,464,999 9/ 1969 Lemieux et al 260302A ALEX MAZEL, Primary Examiner R. I. GALLAGHER, Assistant Examiner U.S. Cl. X.R. 

